Primary infection with varicella-zoster virus (VZV) causes chickenpox, and reactivation of the virus from latency results in zoster. We have previously identified a cellular protein, insulin-degrading enzyme (IDE), that interacts with a VZV glycoprotein, gE and functions as a receptor for entry of the virus into cells. VZV gE interacts with glycoprotein I and the two proteins form a complex on the surface of the virus and on virus-infected cells. In 2009, we found that gE was essential for growth of the virus;a VZV mutant deleted for gE could only be grown in cells expressing gE. VZV lacking the IDE binding domain of gE (amino acids 32-71) grew to peak titers nearly equivalent to parental virus;however, the VZV mutant was impaired for cell-to-cell spread and for infectivity with cell-free virus. VZV lacking the IDE binding domain of gE was not impaired for virus maturation or transport to the surface of the cell. VZV deleted for a region of gE (amino acids 163-208) that binds glycoprotein I could not replicate in cell culture unless grown in cells expressing gE. We conclude that the IDE binding domain is important for efficient cell-to-cell spread and infectivity of cell-free virus. VZV immediate-early 63 protein (IE63) is abundantly expressed during both acute infection in cell culture and latent infection in human ganglia. Previously we showed that IE63 is critical for replication (growth) of virus in cell culture and for establishment of latency in animals. The mechanism by which VZV IE63 is important for virus growth in vitro and latent infection in vivo is not known. In 2009 we found that VZV IE63 interacts with human antisilencing function 1 protein (ASF1). ASF1 is a part of a complex of proteins that is important for assembly of nucleosomes, protein structures on DNA that help to regulate expression of genes from the DNA. IE63 bound to ASF1 and colocalized with ASF1 in cells expressing IE63 and in VZV-infected cells. IE63 colocalized with ASF1 in both lytic and latent VZV-infected enteric neurons. ASF1 exists in two forms, ASF1a and ASF1b, in mammalian cells. IE63 preferentially bound to ASF1a, and the amino-terminal 30 amino acids of ASF1a were critical for its interaction with IE63. VZV IE63 amino acids 171 to 208 and putative phosphorylation sites of IE63, both of which are critical for virus replication and latency in animals, were important for the interaction of IE63 with ASF1. ASF1 interacts with histones and other proteins to form nucleosomes on replicating DNA. Histones are proteins that control gene expression by DNA. We found that IE63 increased the binding of ASF1 to histone H3.1 and H3.3, which suggests that IE63 may help to regulate levels of histones in virus-infected cells. Since ASF1 is important for depositing or removing histones during gene expression, the interaction of VZV IE63 with ASF1 may help to regulate virus or cellular gene expression during replication of VZV or during latent infection with VZV.